Docetaxel is a representative of the taxoid family. [(2R,3S)-N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13-ester with 5β-20-epoxy-1,2α, 4,7β,10β, 13α-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, trihydrate, the active ingredient in Taxotere®, Rhone-Poulenc Rorer, Collegeville, Pa., USA] The compound may be prepared through synthesis from its chemical precursor, naturally present in the renewable needle biomass of yew plants.
Docetaxel is the most effective agent for the treatment of metastatic breast cancer. Currently, practical use has confirmed that docetaxel has high activity also against non-small-cell and small-cell lung, ovarian, head, neck and gastric cancers; as well as melanoma, and soft tissue sarcomas. It promotes the assembly of and stabilizes microtubules and thus inhibits their depolymerization. Docetaxel is highly protein bound, namely, to α1-acid glycoprotein, albumin and lipoproteins. The pharmacokinetic profile is characterized by the initial rapid distribution of docetaxel to the peripheral compartments and in a later phase, the slow efflux of docetaxel from said peripheral compartments.
Docetaxel is highly lipophilic and poorly soluble in water. Taxotere® is a formulation in single-dose vials containing 20 mg (0.5 mL) or 80 mg (2.0 mL) docetaxel (anhydrous). Each ml of this product contains 40 mg docetaxel (anhydrous) and 1040 mg polysorbate 80. The diluent for Taxotere® contains 13% ethanol in water-for-injection.
The safety pattern of Taxotere® includes a premedication regimen. All patients should be premedicated with oral corticosteroids to reduce the severity of fluid retention and hypersensitivity reactions. Other less severe side effects include neurotoxicities, cutaneous reactions, alopecia and asthenia.
Docetaxel is now challenging the role of old agents in the treatment of cancer and is at present approved after failure of other chemotherapy. For example, docetaxel has proven to be the most effective drug against liver metastases. In clinical trials, patients with metastatic breast cancer exhibit response rates for first-line docetaxel treatment at a dose of 100 mg/m2 exceeding those for paclitaxel at doses <250 mg/m2.
The combination of doxorubicin and paclitaxel has entered clinical trials for treatment of patients with breast cancer. There are grounds for assuming that pharmacokinetic interactions between paclitaxel and doxorubicin can intensify anthracycline cardiotoxicity. Docetaxel in contrast has no influence on the pharmacokinetics of doxorubicin. Therefore docetaxel is the number one candidate for use with doxorubicin in clinical trials (C. L. Vogel, J-M. Nabholtz, The Oncologist, 1999, v. 4, p. 17–33; J. E. Cortes, R. Pazdur, J. Clin. Oncology, 1995, v. 13, p. 2643–2655).
Doxorubicin, an anthracycline water-soluble antibiotic, continues to be an important agent of first-line chemotherapy in the treatment of a variety of solid and hematopoieitic tumors. Doxorubicin is isolated from Streptomyces peucetius var. caesius. The chemical name for doxorubicin is {(8S,10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-8-glycolyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphtacenedione hydrochloride, the active ingredient in Adriamycin®, Pharmacia, Sweden}. Adriamycin® contains 50 mg doxorubicin hydrochloride, 250 mg lactose monohydrate, 5 mg methyl para-hydroxybenzoate in dry form.
The efficacy of doxorubicin is complicated by its dose-limiting toxicity, chronic or acute cardiotoxicity and a spontaneous or acquired resistance. It needs to be emphasized that doxorubicin has a certain affinity for phospholipids and the development of resistance appears to be linked to some membrane alterations. At present, the antiproliferative and cytotoxic effects of doxorubicin are believed to be connected with the DNA synthesis inhibition, free radical formation and lipid peroxidation, DNA binding and DNA cross-linking, direct membrane effects.
Trials with incorporation of doxorubicin into combination regimens for the treatment of breast cancer has exhibited modest survival rates for women with metastatic disease.
Drug resistance, both intrinsic and acquired, is fundamental reason for the clinical failure of this compound in breast cancer treatment. Nevertheless, the vast clinical experience gathered so far shows doxorubicin as a well-tolerated and effective drug for most anthracycline-sensitive tumors (D. A. Gewirtz, Biochem. Pharmacol., 1999, v. 57, No. 7, p. 727–741; Vogel and Nabholtz, supra)
Mitoxantrone is a synthetic antracenedione cytotoxic agent derived from the anthraquinone dye ametandrone having structural similarities to doxorubicin. It has a mechanism of action similar to the anthracyclines. Mitoxantrone intercalates in DNA and inhibits DNA synthesis. The drug's antitumor activity is also attributed to its interaction with DNA topoisomerase II.
Mitoxantrone is the active ingredient in Novantrone®, Wyeth Lederle. Novantrone® is a concentrate for infusions, 2 mg/ml. Each ml of concentrate contains 2 mg mitoxantrone hydrochloride, 8 mg sodium chloride, 0.05 mg sodium acetate, 0.46 mg acetic acid, and 0.15 mg sodium sulfate. Mitoxantrone exhibits clinical efficacy in the treatment of leukemia, lymphoma and breast cancer. It is also effective for palliative treatment of hepatic, advanced ovarian carcinoma and hormone-resistant prostate cancer.
The cumulative doses of mitoxantrone can provoke cardiotoxicity and immunosuppresion. Patients having a history of anthracycline therapy can suffer from congestive heart failure (D. Faulds et al., Drugs, 1991, v. 41, No. 3, p. 400–449).
The modern trends in the combat of cancer are challenging the main role of monotherapy in the treatment of patients. Clinical experience suggests a great potential of combination therapy in the adjuvant setting. The creation of effective therapeutic options for the adjuvant setting however requires the development of a new formulation strategy for water insoluble compounds, in order to maximize the potential of the drugs.
In the last years, drug formulations based on nutritional emulsion products have been used. Such formulations need to be adjusted with significant drug loading and to be supplemented by emulsifiers. The formulations must be strictly specified in droplet size distribution. This complicates manufacturing and requires high-pressure homogenization of the lipid emulsions. Moreover, several technical issues need to be addressed, such as the long-term stability and the elimination of the possibility of drug precipitation upon dilution (L. Collins-Gold, et al., Modem Drug Discovery, 2000, Vol. 3, No. 3, p. 44–46, 48).
In co-pending applications (U.S. Ser. No. 10/098,873 and PCT/SE02/00380) the present inventors have disclosed N-Retinoyl-L-cysteic acid, N-Retinoyl-L-homocysteic acid, N-Retinoyl-L-cysteinesulfinic acid, as well as sodium salts of these compounds.
In the present patent application, the inventors disclose novel isoforms of N-Retinoyl-L-cysteic acid, N-Retinoyl-L-homocysteic acid, N-Retinoyl-L-cysteinesulfinic acid, their esters and amides, as well as salts thereof. These novel compounds exhibit cell growth inhibiting properties and in addition to this, also make it possible to manufacture new micellar formulations of poorly water soluble cytotoxic compounds, such as paclitaxel and docetaxel, exhibiting improved solubility and therapeutical efficacy and new micellar formulations of doxorubicin and mitoxantrone, demonstrating improved therapeutic efficacy.